The treatment of cancer by administration of ATP has been disclosed in two U.S. patents and their European and Japanese counterparts. U.S. Pat. No. 4,880,918 and European patent No. 0 100 022 to Rapaport teach and disclose the anti-tumor activities of ATP. These patents outline methods for the killing of human tumors by exposing them to ATP for periods of at least 48 hours (see column 3 lines 41, 45 and 51, column 5 line 37, column 6 lines 23, 25 and 45, column 7 line 48, column 9 line 9, and claim number 3 of U.S. Pat. No. 4,880,918). European patent 0 100 022 contains similar disclosure. U.S. Pat. No. 5,049,372 and its parallel European patent No. 0 352 477 B1 to Rapaport teach and disclose the administration of ATP in the treatment of cancer cachexia and inhibition of weight loss resulting from cancer cachexia. Based on the teachings of these patents and after the issue of these patents, the administration of ATP in the treatment of advanced, non-resectable cancers was utilized in human clinical trials.
Three clinical trials have examined the effects of continuous intravenous infusions of ATP in advanced cancer patients (Haskell et al., Phase I trial of extracellular adenosine 5′-triphosphate in patients with advanced cancer. Medicinal and Pediatric Oncology 1996; 27(3):165-173; Mendoza et al., Adenosine triphosphate (ATP) for advanced non-small cell lung cancer (NSCLC): A Phase II multicenter study. Proceedings Amer Soc Clin Oncology 1996; 15:A1238; Haskell et al., Phase II study of intravenous adenosine 5′-triphosphate in patients with previously untreated stage IIIB and Stage IV non-small cell lung cancer. Invest New Drugs 1998; 16(1):81-85; Agteresch et al., Randomized Clinical Trial of adenosine 5′-triphosphate in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2000; 92(4):321-328; Agteresch, Dagnelie et al., Pharmacokinetics of intravenous ATP in cancer patients. Eur J Clin Pharmacol 2000; 56:49-55.). The published results of these trials provide information about the toxicity, pharmacokinetics, anticachectic and antitumor actions of ATP.
Study One: Haskell et al., (1996, supra). In the initial Phase I/II clinical trial, ATP was administered as a continuous intravenous infusion for 96 hr, once every 4 weeks, at rates of 50, 75 or 100 mcg/kg/min (Haskell et al., 1996, supra). The trial included 14 men with advanced, non-resectable cancer, eight of whom suffered from stage IIIB/IV non-small cell lung cancer. Most of the patients were chemotherapy-naïve. One patient received one infusion; 4 received 2 infusions; 6 received 3 infusions; 1 received 4 infusions; and 2 received 6 infusions.
The dose-limiting toxicity seen in this study was a cardiopulmonary reaction characterized by tightness of the chest and dyspnea that resolved shortly after discontinuing the ATP infusion. This reaction was seen in all three patients (100%) infused at 100 mcg/kg/min; in 3 of 6 (50%) patients infused at 75 mcg/kg/min; and, in 4 of 11 patients (36%) who received 50 μg/kg/min. In some cases, this reaction was accompanied by electrocardiographic changes suggestive of myocardial ischemia. Less frequent or less prominent adverse effects that may, or may not, have been related to ATP treatment were injection site reactions (“local reactions,” pain and phlebitis), hypoxia, hypotension, ECG abnormalities, nausea and/or emesis, abdominal pain, dizziness, headache, anxiety, back or neck pain, anemia, and leukopenia. In summary, 21% of all adverse events recorded in this phase I/II trial were grade 3 or 4 (defined as severe or life-threatening). These included 6 events of dyspnea, 2 events of hypoxia, 5 events of chest pain, 1 event of hypotension, 2 events of nausia/emesis, 1 event of dizziness, 1 event of grade 3 headache and one event of grade 3 anxiety. 79% of all adverse events recorded were of grade 1 or 2 (defined as mild or moderate). Patients required hospitalization for at least 4 days once every four weeks for the purpose of the monitored ATP administration.
With respect to the pharmacokinetic properties of ATP, Haskell et al., (1996, supra) measured the whole blood concentrations of ATP of 18 subjects before and at 24, 48, 72, and 96 hours during and after infusions at rates of 50, 75, or 100 mcg/kg/min. The ATP concentrations were found to vary widely but in general, they increased 30%-40% after 4 hours and the highest blood concentrations were seen at 24 hours of infusion. These concentrations averaged 63%, 67%, and 113%, respectively, higher than the pretreatment values of blood ATP levels. The blood concentrations of ATP were relatively constant or slightly declined during the interval between 24 and 96 hours of the infusion. Little data are available concerning the decay of ATP concentrations post-infusion.
These authors concluded that prolonged infusions of ATP are feasible with acceptable toxicity and that 50 mcg/kg/min is both the maximum tolerated dose and the most appropriate dose rate for subsequent Phase II testing of 96-hours infusions of ATP in patients with advanced cancers.
Study Two: Mendoza et al., (1996, supra), and Haskell et al., (1998, supra). The second human clinical trial conducted by Mendoza et al., (1966, supra), and Haskell et al., (1998, supra), was a Phase II multicenter study of 15 chemotherapy-naïve, stage IIIB/IV non-small cell lung cancer patients. These patients were continuously infused at rates of 50 or 65 mcg/kg/min of ATP for 96 hours, once every 4 weeks (Mendoza et al., 1996, supra; Haskell et al., 1998, supra). Two patients received 1 infusion; 8 received 2 infusions; 4 received 4 infusions; and 1 received 7 infusions.
A large proportion of the patients in this study experienced a variety of adverse effects, including chest pain, dyspnea, coughing, anxiety, injection site pain, chest tightness, headache, insomnia, and hot flashes. Almost one-half of the patients exhibited abnormal electrocardiograms. In some patients, there were minor reductions in hematocrit, hemoglobin, total protein, albumin, sodium, and calcium and minor increases in serum glucose. No significant hematologic, renal, hepatic, or gastrointestinal toxicity was noted. Six patients reported severe (grade 3) adverse effects and two patients had life-threatening (grade 4) dyspnea. All patients were hospitalized for at least 4 days during each of the monitored 96 hours infusion cycles.
Although no significant tumor shrinking was observed, the majority of patients exhibited stable disease after treatment with ATP. In addition, beneficial effects were seen on weight gain, performance status, and the overall survival of patients with non-small cell lung cancer.
Study Three: Agteresch et al., (2000, supra) and Agteresch, Dagnelie et al., (2000, supra). The third trial was a randomized, open label Phase III study of 52 assessable, previously treated, refractory, stage IIIB/IV non-small cell lung cancer patients who failed previous chemotherapy and/or radiation therapy. The patients were randomized into two groups. One group of 25 patients received best supportive care and infusions of ATP while the other group of 27 patients received only best supportive care. The ATP-treated patients received ten 30-hours infusions, the first seven at 2-week intervals and the last three at 4-week intervals. In each case, the infusion was started at 20 mcg/kg/min and increased every 30 min by mcg/kg/min until adverse effects developed or a maximum dose of 75 mcg/kg/min was reached. If adverse effects developed, the dose was reduced stepwise until the adverse effects disappeared. Eleven patients received 1-3 infusions; five received 4-6 infusions; and 12 received 7-10 infusions of ATP.
The adverse experiences seen during treatment were generally mild or moderate and consisted of chest discomfort, urge to take a deep breath, flushing, nausea, lightheadedness, headache, sweating, anxiety, and palpitations. More pronounced side effects were injection site reactions and dyspnea. In patients with chest discomfort, electrocardiograms did not exhibit changes suggestive of myocardial ischemia. All side effects resolved within minutes of lowering the rate of ATP infusion. Of all adverse events recorded in this trial, 81 were of grade 1 (mild), 5 of grade 2 (moderate), none of grade 3 (severe) and 5 were of grade 4 (life threatening). Patients were hospitalized for 1 or 2 days during the monitored infusions of ATP, which were administered at 2 or 4 weeks intervals.
In this study, ATP administration was associated with beneficial effects on body weight and voluntary muscle strength and with improvements in Quality of Life domains. Thus, the authors concluded that ATP shows promise as an agent for the palliation of cancer cachexia.
It is therefore concluded that all prior art related to issued patents and detailed publications of three human clinical trials, established a particular protocol of ATP administration in advanced cancer patients. Such a protocol includes continuous intravenous infusions of ATP for periods longer than 24 hours during which time the patient is being hospitalized. The continuous infusions are administered for multiple treatment cycles every 2-4 weeks. During these infusion protocols some grades 3 and 4 (severe and life threatening) toxicity have been recorded.